Soft Tissue Sarcoma

Epidemiology

• RARE —> 10,000 new cases/year
• Mortality rate → < 50%
• Diagnosed at an early stage → curable
• Extensive local / metastatic → rarely curable
• Recent increase in incidence ( more in women )

Etiology and Genetics

Molecular Abnormalities

• Syndromes asspcoated with Sarcoma
  • Neurofibromatosis
    • Peripheral Nerve sheath tumor
    • 17q11 mutation
  • Gardners Syndrome
    • Familial Polyposis
    • Desmoid tumor
    • Autosomal Dominant
  • Li-Fraume Syndrome
    • Soft tissue and bone sarcoma
    • P53 gene
  • Retinoblastoma survivors
    • RB1 gene

GIST and Desmoid tumors —> Specific oncogenic mutation

• GIST
  • KIT
  • Platelet-derived growth factor-α (PDGFRA) gene mutations
• Desmoid tumors
  • APC/beta-catenin gene mutations
  • Cytology → bland fibrous neoplasms
  • Origin → musculoaponeurotic structures
    • throughout the body
  • The term desmoid, coined by Muller in 1838
    • Derived from the Greek word desmos ( tendonlike )

• Most of adult spindle cell and pleomorphic sarcomas
  • Nonspecific mutations
  • High prevalence of Rb-1
  • p53 alterations
  • Deletions of cyclin-dependent kinase inhibitor-2A (CDKN2A) gene
  • MDM2 amplifications
  • Germ-line mutations in p53 in Li-Fraumeni syndrome
  • Genetic predisposition to
    • Soft tissue sarcoma
    • Neurofibromatosis (NF)
    • Familial adenomatous polyposis (FAP)
• Survivors of retinoblastoma with Rb gene abnormality
  • Often develop tumors later in life
  • Mostly soft tissue sarcomas of the head and neck
  • The increased risk of a second primary is enhanced by radiotherapy in a dose-dependent fashion
    • Soft tissue sarcoma
      • beginning at 5 Gy
      • 10.7-fold if > 60 Gy
• FAP
  • A subset of Gardner's syndrome
  • Intra-abdominal desmoids
    • Low-grade fibrosarcomas
• Post–irradiation-induced sarcomas
  • Risk is also influenced by chemo administration
  • Reputation for originating close to the penumbra of radiotherapy fields
    • Incomplete damage in normal tissues
    • Uncommon
    • Poor prognosis

• Lymphedema
  • A factor for lymphangiosarcom
• Trauma
  • Not causative
  • Draw attention leads to diagnosis of mass
  • Chemical agent

Phenoxyacetic acids found in some herbicides
Chlorophenols (present in some wood preservatives)
Thorotrast, vinyl chloride, and arsenic (including Fowler's 1% arsenic solution)
Cytogenetic Abnormalities
Usually associated with high-grade tumors
Ewing's sarcoma (primitive neuroectodermal tumor)
t(11;22)(q24;q11.2-12)
Synovial sarcoma
t(X;18)(p11.2;q11.2).
Many other studies of genetic abnormalities
Abnormalities of INK4A (coding for p16 and p19ARF on 9p21)
INK4B
poor survival
Myxoid and round cell liposarcomas
TLS-CHOP fusion protein
links these two forms of liposarcoma with one another despite their strikingly different morphologic characteristics.
Pathologic Classification
Clinically nondistinctive
Little evidence that these lesions arise from their mature (differentiated) tissue counterparts
Many liposarcomas arise at sites devoid of adipose tissue
Most rhabdomyosarcomas develop in locations that lack voluntary muscle
No evidence to support the concept of a primitive mesenchymal stem cell as the precursor
A likelier explanation
Given set of genes that programs mesenchymal differentiation in any type of mesenchymal cell may give rise to almost any mesenchymal neoplasm
Soft tissue tumors
Benign
Benign vs Mailgnant → 100:1
Malignant
Borderline
Benign and malignant cases may be confused
Particularly in small biopsy samples.
Liposarcoma
Well differentiated
Dedifferentiated
Myxoid
Round cell
Pleomorphic
Totally different biologies and patterns of behaviour
Myogenic differentiation in pleomorphic sarcomas
Associated with a substantially increased risk of metastasis
Local invasiveness
Pattern of metastasis
Mostly → hematogenous
Lymph node metastases → uncommon
Except for childhood sarcoma
Resection of LN in selected cases may prolong survival
Grading of Sarcoma
Most critical piece of information the pathologist can provide to the clinician is histologic grade
Grade → The most important prognostic factor for adult soft tissue sarcoma
Pathologic features that define grade
Cellularity
Histologic type and subtype
Differentiation
Pleomorphism
Necrosis → most important
Number of mitoses → most important
A four-grade system (Broders)
A three-grade system (low, intermediate, high)
French Federation of Cancer Centers Sarcoma Group
A binary system (high vs. low)
To define a practical grading system→ (EORTC)
Studied the histologic features
282 patients
Adjuvant chemotherapy
What predicts survival?
Mitotic count (fewer than 3; 3 to 20; and more than 20 mitoses per 10 consecutive high-power fields)
The presence or absence of necrosis
Tumor size
Is small sampling
Use radiologic and molecular parameters
Extent of necrosis in radiology
MRI
magnetic resonance spectroscopy
To assess tumor necrosis
Chemotherapy response
Grading in sarcoma
Mitotic index is difficult to determine on limited core biopsy material
MIB-1 scores of proliferation are more reproducible
better predictive value than grading using mitotic index
Other molecular parameters associated with high grade
Mutation of p53
Nuclear overexpression of p53
High Ki-67 proliferation index
In GISTs the type of mutation has been reported as a predictor for survival independent of mitotic index and size
Differential Diagnosis
41% → extremities
29% in lower limb
36% → intra-abdominal
Visceral (21%)
Retroperitoneal (15%) lesions.

Distribution by site of soft tissue sarcomas in
Differential diagnosis of a soft tissue mass
Benign lesions
Primary
Melanoma
Lymphoma
Metastatic carcinoma
The most useful immunohistochemical markers
Intermediate filaments ( size between actin and myosin; cytoplasmic filaments )
Vimentin
Keratin
Desmin
Leukocyte common antigen, S-100
Fusion gene translocations include 11 different gene fusions involving the EWS gene or EWS family members
Found in five different sarcomas
Molecular genetic techniques is easier →
Reverse transcriptase-PCR ( polymerase chain reaction )
Fluorescence in situ hybridization (FISH)
The three most common histopathologic subtypes
MFH
M(ixed?) fibrous Hystiosarcoma
Liposarcoma
Leiomyosarcoma
Extremities → liposarcoma, MFH, synovial sarcoma, and fibrosarcoma
Retroperitoneal location → well-differentiated and dedifferentiated liposarcoma and leiomyosarcoma
Visceral location → GISTs are found most commonly.
GIST previously were classified as leiomyosarcomas or leiomyoblastomas
But GIST → No markers of myogenic differentiation
Mesenchymal neoplasms showing differentiation toward the interstitial cells
Expression of the receptor tyrosine kinase KIT
Pattern of recurrence
Intra-abdominal
Liver metastasis
GU → Leiomyosarcoma
Paratesticular → Rhabdomyosarcoma
→ young men
Pediatric → small round-cell sarcomas
Rhabdomyosarcoma
Ewing's sarcoma
Primitive neuroectodermal tumor spectrum
Clinicopathologic Features of Specific Types of Benign and Malignant Soft Tissue Tumors
Tumors of Fibrous Origin
Beingn Fibrous Tumors
Composed of an admixture of fibroblasts and myofibroblasts
Nodular Fasciitis
Benign
Young age
Grow rapidly over several weeks → 1 to 2 cm ; rarely > 5 cm
Pain & tenderness are common
Upper extremity
volar aspect of the forearm
Fibroma
Simple excision
Propensity of recurrence if inadequate excision
Elastofibroma
Benign
Rare
Slow-growing
Lower portion of the scapula between the scapula and chest wall
Associated with repetitive manual tasks → reactive lesions
May be
Large
Bilateral
Within families!
Superficial Fibromatosis
Benign
From the fascia or aponeuroses
Small and slow growing
Palmar fibromatosis → flexion contractures (Dupuytren's contracture)
Tendency to recur
Plantar fibromatosis (Ledderhose's disease)
Penile fibromatosis (Peyronie's disease)
Pain and curvature of the penis on erection
Less common
Desmoid Tumor = aggressive fibromatosis
Deep-seated fibrous neoplasms
Three groups
Sporadic
Associated with FAP
Multicentric or familial
Abdominal wall in women who had recently been pregnant
Rare, slow-growing
Any site
By location
Extra-abdominal (60% of cases)
Abdominal wall (25%)
Intra-abdominal (15%)
In the retroperitoneum → aggressive
Invasion and progressive growth
Do not metastasize
Large infiltrative masses
Wide excision
If not → recur repeatedly
Balance between wide margin and chance of use of low dose chemo
Function preservation
Gardner's syndrome
Abdominal and retroperitoneal desmoids
Clearly linked to APC gene
Fibromas
Osteomas
Epidermoid cysts
FAP
Fibrosarcoma
Uncommon
Thigh / trunk
Rarely metastasizes
Classic herringbone pattern

Rarely → in ovary and other unusual sites ( trachea )
Low-grade tumors occur in the extremities.
Fibrohistiocytic Tumors
Histiocytes term → for their ppearance
None → with true histiocytic differentiation.
Fibrous Histiocytoma
Benign
Solitary, slow-growing nodules
One third → multiple
Fibroblastic and histiocytic cells
Cartwheel or storiform pattern

Dermatofibromas or sclerosing hemangiomas
SKIN
Superficial lesions → simple excision
Deeper lesions → wider margin of normal tissue to prevent local recurrence.
Does not stain positive for CD34
Xanthoma
Xanthoma refers to a collection of lipid-laden histiocytes and is seen in diseases associated with hyperlipidemia. These lesions generally occur in cutaneous or subcutaneous locations but may involve deep soft tissues. Presumably, xanthomas are reactive lesions.
Dermatofibrosarcoma Protuberans
Low-grade sarcoma
Recur locally
Rarely metastasizes
Relatively monomorphous, mononuclear, spindle cell
Involving both dermis and subcutis
Anywhere in the body
Beginning as a nodular cutaneous mass
Slow and persistent growth
Large lesions often are associated with satellite nodules
Similar to benign fibrous histiocytoma histologically but grows
In a more infiltrative pattern
Spreading along connective tissue septa
Stains positive for CD34
Mostly a ring chromosome
translocated portions of 17 and 22
A consistent gene fusion product
Creates an apparent platelet-derived growth factor autocrine loop
Tumor's imatinib sensitivity ( GLEEVEC )
Imatinib ⇒ blocks platelet-derived growth factor receptor action
50% recur after simple excision
Wide resection margin⇒ the local recurrence rate is 5% or less
Areas of increased pleomorphism and mitotic activity occur → especially in recurrent lesions
Metastases occur rarely to lung or to lymph nodes and typically only when fibrosarcomatous change is detected in the primary or recurrent lesion
Locally aggressive nature, these lesions may ultimately lead to amputation or even death because of extensive invasion
A variant with melanin pigmentation (Bednar's tumor)
Malignant Fibrous Histiocytoma= high-grade undifferentiated pleomorphic sarcoma
The term MFH was first introduced in 1963
to describe a group of malignant soft tissue tumors with a fibrohistiocytic appearance
the most commonly diagnosed extremity sarcoma
Subtypes
Myxoid
Giant cell
Inflammatory
Angiomatoid
Pleomorphic
Specific line of differentiation
Peak incidence in the seventh decade
Painless mass
Most common site
1. lower extremity
2. upper extremity
It is now termed high-grade undifferentiated pleomorphic sarcoma, according to the latest World Health Organization fascicle.
Tumors of Adipose Tissue
Lipoma
Most common benign soft tissue neoplasm
Subcutaneous tissue
Trunk and proximal limbs ( most frequent sites )
Also in mediastinum or retroperitoneum
BUT seemingly mature fatty neoplasms in the retroperitoneum should be regarded with suspicion because most are well-differentiated liposarcoma.
Solitary, soft, and painless and grow slowly
2% to 3% multiple
Familial usually
Lipomatosis
Overgrowth of mature adipose tissue that grows in an infiltrating pattern.